Cone-beam CT (CBCT) offers an important new modality for image-guided interventions. Its implementation on a mobile C-arm presents an opportunity to develop a high-performance intraoperative imaging and guidance system and investigate the benefits to surgical performance in challenging interventional tasks. In head and neck (H&N) surgery, infiltrative disease within a complex environment of critical structures (e.g., the optic nerves, carotid arteries and brain) poses a major challenge to surgical performance in the absence of intraoperative imaging. While conventional image-guided surgery (IGS) using real-time tracking and navigation relative to preoperative images has offered an important advance, its value is largely limited to resection of bony neoplasms in the context of rigid (non-deforming) skeletal anatomy. A broad spectrum of H&N surgeries - particularly those targeting soft-tissue lesions with deformation likely in the course of therapy (e.g., herniation of orbital and intracranial structures) - requires intraoperative imaging to reap the full benefit of IGS. We hypothesize that intraoperative CBCT offering sub-mm 3D spatial resolution and soft-tissue visibility will maximize surgical performance in target ablation, minimize complications to critical structures, and extend the applicability of IGS across the full range of H&N interventions. We propose to develop, characterize, and deploy a high-performance image guidance system based on C-arm CBCT as follows: 1.) Develop a fully integrated surgical guidance system based on C-arm CBCT, realtime tracking, and 3D deformable image registration; 2.) Quantitatively evaluate the benefits to surgical performance in challenging interventional tasks, including ethmoid sinus ablation, trans-sphenoid approach to the CNS, and skull base lesion excision; and 3.) Investigate system performance in pre-clinical deployment in patient studies under research protocol, including multi-modality intraoperative CBCT and MRI. High-performance IGS bas ed on intraoperative CB CT offers to: i.) improve surgical performance (maximize sensitivity and specificity in the ablation of challenging targets); ii.) expand the application of surgery to cases that would be conventionally inoperable; and iii.) support the development of novel surgical therapeutics (e.g., robot-assisted surgery, photodynamic therapy, and precise targeting using chemical or biological agents) that require a high degree of geometric precision provided by intraoperative imaging. [unreadable] [unreadable] [unreadable]